Wang Weijia, Zhang Yan, Yuan Yong, Yuan Runqiang, Yang Youye, Zhang Xiuming, Wen Dongmei, Huang Fuda, Wang Jinshu
Department of Laboratory Diagnosis, Sun Yat-Sen University Affiliated Zhongshan Hospital, Sun Yat-Sen University, Zhongshan 528403, PR China.
Key Laboratory of Diagnostic Medicine Designated by The Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, PR China.
Oncotarget. 2017 Jul 22;8(41):69924-69933. doi: 10.18632/oncotarget.19457. eCollection 2017 Sep 19.
NSC67657 is a new steroid drug that induces monocytic differentiation of acute myeloid leukemia cells. Here, we demonstrate that NSC67657 has opposing effects on expression of downstream targets of inhibitor of β-catenin and TCF (ICAT) and Wnt signaling in HL60 cells. ICAT binds to β-catenin, and this interaction is further increased in NSC67657-differentiated cells. ICAT overexpression decreases expression of Wnt downstream targets and increases sensitivity of HL60 cells to NSC67657, while ICAT silencing increases Wnt signaling and delays the NSC67657-induced cell differentiation. In addition, pharmacological inhibition of Wnt/β-catenin signaling increases the NSC67657-induced cell differentiation, while activation of Wnt/β-catenin signaling inhibits the differentiation, indicating Wnt/β-catenin signaling inhibits NSC67657-induced monocytic differentiation of HL60 cells. Our data demonstrate the opposing roles of ICAT and Wnt signaling in the NSC67657-induced monocytic differentiation, and suggest that ICAT and Wnt signaling may serve as therapeutic targets for leukemia chemotherapy.
NSC67657是一种新型甾体药物，可诱导急性髓系白血病细胞向单核细胞分化。在此，我们证明NSC67657对HL60细胞中β-连环蛋白和TCF抑制剂（ICAT）的下游靶点表达以及Wnt信号传导具有相反的作用。ICAT与β-连环蛋白结合，并且这种相互作用在NSC67657诱导分化的细胞中进一步增强。ICAT过表达降低Wnt下游靶点的表达，并增加HL60细胞对NSC67657的敏感性，而ICAT沉默则增强Wnt信号传导并延迟NSC67657诱导的细胞分化。此外，Wnt/β-连环蛋白信号传导的药理学抑制增强了NSC67657诱导的细胞分化，而Wnt/β-连环蛋白信号传导的激活则抑制了分化，表明Wnt/β-连环蛋白信号传导抑制了NSC67657诱导的HL60细胞向单核细胞的分化。我们的数据证明了ICAT和Wnt信号传导在NSC67657诱导的单核细胞分化中的相反作用，并表明ICAT和Wnt信号传导可能作为白血病化疗的治疗靶点。
